Perspective paper Plants as a source of anti-cancer agents

Plant-derived compounds have been an important source of several clinically useful anti-cancer agents. These include vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, etoposide, derived from epipodophyllotoxin, and paclitaxel (taxol A number of promising new agents are in clinical development based on selective activity against cancer-related molecular targets, including flavopiridol and combretastin A4 phosphate, while some agents which failed in earlier clinical studies are stimulating renewed interest.


Summary
Plant-derived compounds have played an important role in the development of several clinically useful anti-cancer agents. These include vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, etoposide, derived from epipodophyllotoxin, and paclitaxel (taxol ® ). Several promising new agents are in clinical development based on selective activity against cancer-related molecular targets, including flavopiridol and combretastin A4 phosphate, and some agents which failed in earlier clinical studies are stimulating renewed interest.

Introduction
Plants have a long history of use in the treatment of cancer. Hartwell, in his review of plants used against cancer, lists more than 3000 plant species that have reportedly been used in the treatment of cancer. In many instances, however, the "cancer" is undefined, or reference is made to conditions such as "hard swellings", abscesses, calluses, corns, warts, polyps, or tumors, to name a few. These symptoms would generally apply to skin, "tangible", or visible conditions, and may indeed sometimes correspond to a cancerous condition. Many of the claims for efficacy in the treatment of cancer, however, should be viewed with some skepticism because cancer, as a specific disease entity, is likely to be poorly defined in terms of folklore and traditional medicine. This is in contrast to other plant-based therapies used in traditional medicine for the treatment of afflictions such as malaria and pain, which are more easily defined, and where the diseases are often prevalent in the regions where traditional medicine systems are extensively used. However, despite these observations, it is significant that over 60% of currently used anti-cancer agents are derived in one way or another from natural sources, including plants, marine organisms and micro-organisms. Indeed, molecules derived from natural sources (so-called natural products), including plants, marine organisms and micro-organisms, have played, and continue to play, a dominant role in the discovery of leads for the development of conventional drugs for the treatment of most human diseases.
While in past years, cancer has been regarded mainly as a group of diseases afflicting the more developed countries, the incidence of various forms of cancer is now rapidly rising worldwide. Reference to the World Health Organization database on cancer incidence and mortality [http://www.who.int/cancer/resources/incidences/en/] indicates substantial numbers of cases of major cancers in less developed countries (see Table 1). The search for anti-cancer agents from plant sources started in earnest in the 1950s with the discovery and development of the vinca alkaloids, vinblastine and vincristine, and the isolation of the cytotoxic podophyllotoxins (see Section 2). These discoveries prompted the United States National Cancer Institute (NCI) to initiate an extensive plant collection program in 1960, focused mainly in temperate regions. This led to the discovery of many novel chemotypes showing a range of cytotoxic activities, including the taxanes and camptothecins, but their development into clinically active agents spanned a period of some 30 years, from the early 1960s to the 1990s. This plant collection program was terminated in 1982, but with the development of new screening technologies, the NCI revived the collections of plants and other organisms in 1986. This time the focus was on the tropical and sub-tropical regions of the world, but it is interesting to note that no new plant-derived clinical anti-cancer agents have, as yet, reached the stage of general use. However, as described in Sections 3 to 5, a number of agents are in preclinical development. The first agents to advance into clinical use were the so-called vinca alkaloids, vinblastine (VLB) and vincristine (VCR), isolated from the Madagascar periwinkle, Catharanthus roseus G. Don. (Apocynaceae), which was used by various cultures for the treatment of diabetes. These drugs were first discovered during an investigation of the plant as a source of potential oral hypoglycemic agents. While research investigators could not confirm this activity, it was noted that extracts reduced white blood cell counts and caused bone marrow depression in rats, and subsequently it was found that the treatment of mice bearing a transplantable lymphocytic leukemia caused significant life extension. This led to the isolation of VLB and VCR as the active agents, so their discovery may be indirectly attributed to the observation of an unrelated medicinal use of the source plant. It is interesting to note that though the plant was originally endemic to Madagascar, the samples used in the discovery of VLB and VCR were collected in Jamaica and the Philippines. More recent semi-synthetic analogues of these agents are vinorelbine (VRLB) and vindesine (VDS). These agents are primarily used in combination with other cancer chemotherapeutic drugs for the treatment of a variety of cancers. VLB is used for the treatment of leukemias, lymphomas, advanced testicular cancer, breast and lung cancers, and Kaposi's sarcoma, and VCR, in addition to the treatment of lymphomas, also shows efficacy against leukemias, particularly acute lymphocytic leukemia in childhood. VRLB has shown activity against non-small-cell lung cancer and advanced breast cancer. Of over 2069 anti-cancer clinical trials recorded by the NCI as being in progress as of July 2004, over 160 are drug combinations including these agents against a range of cancers.

Plant-Derived Anti-Cancer Agents in Clinical Use
The two clinically-active agents, etoposide (VM 26) and teniposide (VP 16-213), which are semi-synthetic derivatives of the natural product, epipodophyllotoxin (an isomer of podophyllotoxin), may be considered as being more closely linked to a plant originally used for the treatment of "cancer". The Podophyllum species (Podophyllaceae), P. peltatum Linnaeus (commonly known as the American mandrake or Mayapple), and P. emodii Wallich from the Indian subcontinent, have a long history of medicinal use, including the treatment of skin cancers and warts. P. peltatum was used by the Penobscot Native Americans of Maine for the treatment of "cancer", and interest was promoted by the observation in the 1940s that venereal warts could be cured by topical application of an alcohol extract of the dried roots (called podophyllin). The major active constituent, podophyllotoxin, was first isolated in 1880, but its correct structure was only reported in the 1950s. Many closely related podophyllotoxin-like lignans were isolated during this period, and several of them were introduced into clinical trials, only to be dropped due to lack of efficacy and unacceptable toxicity. one reported use in the treatment of "cancer". Paclitaxel, along with several key precursors (the baccatins), occurs in the leaves of various Taxus species, and the ready semi-synthetic conversion of the relatively abundant baccatins to paclitaxel, as well as active paclitaxel analogs, such as docetaxel (Taxotere ® ), has provided a major, renewable natural source of this important class of drugs. Paclitaxel is used in the treatment of breast, ovarian and non-small-cell lung cancer (NSCLC), and has also shown efficacy against Kaposi sarcoma. Paclitaxel has also attracted attention in the potential treatment of multiple sclerosis, psoriasis and rheumatoid arthritis. Docetaxel is primarily used in the treatment of breast cancer and NSCLC. The importance of this class of anti-cancer agents may be judged from the fact that 12 and 23 taxane analogs are in clinical and preclinical development, respectively. In addition, of 2069 cancer clinical trials recorded by the NCI as being in progress as of July 2004, 248 or close to 12% are listed as involving taxane-derived drugs, including 134 with paclitaxel (Taxol ® ), 105 with docetaxel (Taxotere ® ), and 10 with miscellaneous taxanes, either as single agents or in combination with other anti-cancer agents. In addition, 23 taxanes are in preclinical development.
Another important addition to the anti-cancer drug armamentarium is the class of clinically-active agents derived from camptothecin, which is isolated from the Chinese ornamental tree, Camptotheca acuminata Decne (Nyssaceae), known in China as the tree of joy. Camptothecin was discovered from extracts of plants originally collected by the U. S. Department of Agriculture as a possible source of steroidal precursors for the production of cortisone. The extract of C. acuminata was the only one of 1000 of these plant extracts tested for anti-tumor activity which showed efficacy, and camptothecin was isolated as the active constituent. Camptothecin (as its sodium salt) was advanced to clinical trials by the NCI in the 1970s, but was dropped because of severe bladder toxicity. However, extensive research was performed by several pharmaceutical companies in a search for more effective camptothecin derivatives, and   He has established collaborations between the National Cancer Institute and organizations in many countries promoting drug discovery from their natural resources. He has published over 100 papers related to these interests.
David Newman was born in Grays, Essex, UK. Initially he trained as a chemical analyst (Grad. RIC), followed by an M.Sc. in Organic Chemistry (University of Liverpool), and then after time in the UK chemical industry, he obtained a D.Phil. in Microbial Chemistry from the University of Sussex in 1968. Following two years of postdoctoral studies on the structure of electron transport proteins at the University of Georgia, USA, he worked for Smith Kline and French in Philadelphia, Pennsylvania, as a biological chemist predominately in the area of antibiotic discovery. During this time period, he obtained an MS in Information Sciences in 1977 from Drexel University, Philadelphia. He has worked for a number of US-based pharmaceutical companies in natural products-based discovery programs in antiinfective and cancer treatments, and joined the Natural Products Branch of the NCI in 1991. He is responsible for the marine and microbial collection programs of the NCI, and in concert with Gordon Cragg, for the NCI's Open and Active Repository programs. In 2003 he was awarded the NIH Merit Award for his contributions to the development of potential anti-cancer agents from marine and microbial sources. His scientific interests are in the discovery and history of novel natural products as drug leads in the anti-infective and cancer areas, and in the application of information technologies to drug discovery. In conjunction with Gordon Cragg, he has established collaborations between the National Cancer Institute and organizations in many countries promoting drug discovery from their natural resources. He has published over 60 papers, presented over 60 abstracts, holds 17 patents that are related to these interests, is both a UK Chartered Chemist and a UK Chartered Biologist and is also an adjunct full professor at the Center of Marine Biotechnology, University of Maryland.